Benzimidazole compound crystal

ABSTRACT

A novel crystal of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl],sulfinyl]-1H-benzimidazole or a salt thereof of the present invention is useful for an excellent antiulcer agent.

This application is a continuation of application Ser. No. 11/149,903,filed Jun. 10, 2005, which is a continuation of Ser. No. 10/655,114,filed Sep. 4, 2003, which is a continuation of application Ser. No.10/243,329, filed Sep. 13, 2002, which is a continuation of applicationSer. No. 09/674,624, filed Nov. 3, 2000, which application isincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a crystal of a benzimidazole compoundshowing antiulcer action.

BACKGROUND ART

2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof having an antiulcer action is reported inJP-A-61-50978, etc.

There is a demand for a more stable and excellently absorbable antiulceragent.

DISCLOSURE OF INVENTION

Having chiral sulfur in the molecular structure thereof,2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleoccurs in two kinds of optical isomers. After extensive exploration, thepresent inventors succeeded in optically resolving and present inventorssucceeded in optically resolving and crystallizing in the (R)-isomer of2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,for the first time found that this crystal serves satisfactorily as apharmaceutical, made further investigation based on this finding, anddeveloped the present invention.

Accordingly, the present invention relates to:

-   [1] a crystal of    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole    or a salt thereof,-   [2] a crystal of    (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole;-   [3] a crystal according to the above [2] wherein the X-ray powder    diffraction analysis pattern has characteristic peaks at interplanar    spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89,    3.69, 3.41 and 3.11 Angstrom;-   [4] a pharmaceutical composition which comprises the crystal    according to the above [1];-   [5] a pharmaceutical composition according to the above [4], which    is for treating or preventing digestive ulcer;-   [6] a method for treating or preventing digestive ulcer in a mammal    in need thereof which comprises administering to said mammal an    effective amount of the crystal according to the above [1] with a    pharmaceutically acceptable excipient, carrier or diluent;-   [7] use of the crystal according to the above [1] for manufacturing    a pharmaceutical composition for treating or preventing digestive    ulcer, and so forth.

The “salt” of“(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof” includes, for example, metal salts, salts withorganic bases, salts with basic amino acids, and so forth. Preferred arephysiologically acceptable salts.

Metal salts include, for example, alkali metal salts such as sodium saltand potassium salt; and alkaline earth metal salts such as calcium salt,magnesium salt and barium salt. Salts with organic bases include, forexample, salts with trimethylamine, triethylamine, pyridine, picoline,ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,N,N-dibenzylethylenediamine, etc.

Salts with basic amino acids include, for example, salts with arginine,lysine, etc.

The crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof may be a hydrate or not.

Said “hydrate” includes 0.5 hydrate to 5.0 hydrate. Among others, 0.5hydrate, 1.0 hydrate, 1.5 hydrate, 2.0 hydrate and 2.5 hydrate arepreferred. More preferred is 1.5 hydrate.

The crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof can be produced by subjecting2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof to an optical resolution or subjecting2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazoleto an asymmetrical oxidization to obtain the (R)-isomer, followed bycrystallizing the resultant isomer.

Methods of optical resolution include per se known methods, for example,a fractional recrystallization method, a chiral column method, adiastereomer method, and so forth. Asymmetric oxidation includes per seknown methods.

The “fractional recrystallization method” includes a method in which asalt is formed between a racemate and an optically active compound[e.g., (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid,(−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine,cinchonine, (−)-cinchonidine, brucine, etc.], which salt is separated byfractional recrystallization etc., and, if desired, subjected to aneutralization process, to give a free optical isomer.

The “chiral column method” includes a method in which a racemate or asalt thereof is applied to a column for optical isomer separation(chiral column). In the case of liquid chromatography, for example,optical isomers are separated by adding a racemate to a chiral columnsuch as ENANTIO-OVM (produced by Tosoh Corporation) or the DAICEL CHIRALseries (produced by Daicel Corporation), and developing the racemate inwater, a buffer (e.g., phosphate buffer), an organic solvent (e.g.,hexane, ethanol, methanol, isopropanol, acetonitrile, trifluoroaceticacid, diethylamine, triethylamine, etc.), or a solvent mixture thereof.In the case of gas chromatography, for example, a chiral column such asCP-Chirasil-DeX CB (produced by GL Science) is used to separate opticalisomers.

The “distereomer method” includes a method in which a racemate and anoptically active reagent are reacted (preferably, an optically activereagent is reacted to the 1-position of the benzimidazole group) to givea diastereomer mixture, which is then subjected to ordinary separationmeans (e.g., fractional recrystallization, chromatography, etc.) toobtain either diastereomer, which is subjected to a chemical reaction(e.g., acid hydrolysis, base hydrolysis, hydrogenolysis, etc.) to cutoff the optically active reagent moiety, whereby the desired opticalisomer is obtained. Said “optically active reagent” includes, forexample, optically active organic acids such as MTPA[α-methoxy-α-(trifluoromethyl)phenylacetic acid] and (−)-menthoxyaceticacid; and optically active alkoxymethyl halides such as(1R-endo)-2-(chloromethoxy)-1,3,3-trimethylbicyclo[2.2.1] heptane, etc.

2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof is produced by the methods described in JP-A-61-50978,U.S. Pat. No. 4,628,098 etc. or analogous methods thereto.

Methods of crystallization includes per se known methods, for example, acrystallization from solution, a crystallization from vapor, and acrystallization from molten form.

Methods of the “crystallization from solution” include, for example, aconcentration method, a slow cooling method, a reaction method(diffusion method, eletrolysis method), a hydrothermal growth method, afusing agent method, and so forth. Solvents to be used include, doeexample, aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.),halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.),saturated hydrocarbons (e.g., hexane, heptane, cyclohexane, etc.),ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, etc.), nitriles (e.g., acetonitrile, etc.), ketones (e.g.,acetone, etc.), sulfoxides (e.g., dimethylsulfoxide, etc.), acid amides(e.g., N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.),alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), water, andso forth. These solvents may be used singly or in mixtures of two ormore kinds in appropriate ratios (e.g., 1:1 to 1:100).

Methods of the “crystallization from vapor” include, for example, agasification method (sealed tube method, gas stream-method), a gas phasereaction method, a chemical transportation method, and so forth.

Methods of the “crystallization from molten form” include, for example,a normal freezing method (pulling-up method, temperature gradientmethod, Bridgman method), a zone melting method (zone leveling method,float zone method), a special growth method (VLS method, liquid phaseepitaxis method), and so forth.

For analyzing the crystal obtained, X-ray diffraction crystallographicanalysis is commonly used. In addition, crystal orientation can also bedetermined by a mechanical method, an optical method, etc.

A thus-obtained crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof (hereinafter also referred to as “crystal of thepresent invention”) is useful as a pharmaceutical because it showsexcellent “crystal of the present invention”) is useful as apharmaceutical because it shows excellent antiulcer action, gastric acidsecretion-inhibiting action, mucosa-protecting action, anti-Helicobacterpylori action, etc., and because it is of low toxicity. Furthermore, bycrystallizing the (R)-isomer, not only its stability is improved butalso its handling is facilitated so that it can be prepared as a solidpharmaceutical composition with good reproducibility. In addition, whenorally administered, the crystal of the present invention is moreabsorbable and more rapidly shows its action than the racemate. Inaddition, when administered, the crystal of the present invention showsa higher Cmax (maximum blood concentration) and greater AUC (area underthe concentration-time curve) than the racemate, and becomes less likelyto be metabolized partly because of the increased protein-binding rate,thus showing an extended duration of action. The crystal of the presentinvention is therefore useful as a pharmaceutical of low dosage and witha low prevalence of adverse reactions.

The crystal of the present invention is useful in mammals (e.g., humans,monkeys, sheep, bovines, horses, dogs, cats, rabbits, rats, mice, etc.)for the treatment and prevention of digestive ulcer (e.g., gastriculcer, duodenal ulcer, stomal ulcer, Zollinger-Ellision syndrome, etc.),gastritis, reflux esophagitis, NUD (non-ulcer dyspepsia), gastric cancerand gastric MALT lymphoma; Helicobacter pylori eradication; suppressionof upper gastrointestinal hemorrhage due to digestive ulcer, acutestress ulcer and hemorrhagic gastritis; suppression of uppergastrointestinal hemorrhage due to invasive stress (stress from majorsurgery necessitating intensive management after surgery, and fromcerebral vascular disorder, head trauma, multiple organ failure andextensive burns necessitating intensive treatment); treatment andprevention of ulcer caused by a nonsteroidal anti-inflammatory agent;treatment and prevention of ulcer caused by nonsteroidalanti-inflammatory agent; treatment and prevention of hyperacidity andulcer due to postoperative stress; pre-anesthetic administration etc.

The crystal of the present invention is of low toxicity and can besafely administered orally or non-orally (e.g., topical, rectal andintravenous administration, etc.), as such or in the form ofpharmaceutical compositions formulated with a pharmacologicallyacceptable carrier, e.g., tablets (including sugar-coated tablets andfilm-coated tablets), powders, granules, capsules (including softcapsules), orally disintegrating tablets, liquids, injectablepreparations, suppositories, sustained-release preparations and patches,in accordance with a commonly known method.

The content of the crystal of the present invention in thepharmaceutical composition of the present invention is about 0.01 to100% by weight relative to the entire composition. Varying depending onsubject of administration, route of administration, target disease etc.,its dose is normally about 0.5 to 1,500 mg/day, preferably about 5 to150 mg/day, based on the active ingredient, for example, when it isorally administered as an antiulcer agent to an adult human (60 kg). Thecrystal of the present invention may be administered once daily or in 2to 3 divided portions per day.

Pharmacologically acceptable carriers that may be used to produce thepharmaceutical composition of the present invention include variousorganic or inorganic carrier substances in common use as pharmaceuticalmaterials, including excipients, lubricants, binders, disintegrants,water-soluble polymers and basic inorganic salts for solid preparations;and solvents, dissolution aids, suspending agents, isotonizing agents,buffers and soothing agents for liquid preparations. Other ordinarypharmaceutical additives such as preservatives, antioxidants, coloringagents, sweetening agents, souring agents, bubbling agents andflavorings may also be used as necessary.

Such “excipients” include, for example, lactose, sucrose, D-mannitol,starch, cornstarch, crystalline cellulose, light silicic anhydride andtitanium oxide.

Such “lubricants” include, for example, magnesium stearate, sucrosefatty acid esters, polyethylene glycol, talc and stearic acid.

Such “binders” include, for example, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, crystalline cellulose, α-starch,polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan andlow-substitutional hydroxypropyl cellulose.

Such “disintegrants” include (1) crosslinked povidone, (2) what iscalled super-disintegrants such as crosslinked carmellose sodium(FMC-Asahi Chemical) and carmellose calcium (Gotoku Yakuhin), (3)carboxymethyl starch sodium (e.g., product of Matsutani Chemical), (4)low-substituted hydroxypropyl cellulose (e.g., product of Shin-EtsuChemical), (5) cornstarch, and so forth. Said “crosslinked povidone” maybe any crosslinked polymer having the chemical name1-ethenyl-2-pyrrolidinone homopolymer, including polyvinylpyrrolidone(PVPP) and 1-vinyl-2-pyrrolidinone homopolymer, and is exemplified byColidon CL (produced by BASF), Polyplasdon XL (produced by ISP),Polyplasdon XL-10 (produced by ISP) and Polyplasdon INF-10 (produced byISP).

Such “water-soluble polymers” include, for example, ethanol-solublewater-soluble polymers [e.g., cellulose derivatives such ashydroxypropyl cellulose (hereinafter also referred to as HPC),polyvinylpyrrolidone] and ethanol-insoluble water-soluble polymers[e.g., cellulose derivatives such as hydroxypropylmethyl cellulose(hereinafter also referred to as HPMC), methyl cellulose andcarboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol,sodium alginate, guar gum].

Such “basic inorganic salts” include, for example, basic inorganic saltsof sodium, potassium, magnesium and/or calcium. Preferred are basicinorganic salts of magnesium and/or calcium. More preferred are basicinorganic salts of magnesium. Such basic inorganic salts of sodiuminclude, for example, sodium carbonate, sodium hydrogen carbonate,disodium hydrogenphosphate, etc. Such basic inorganic salts of potassiuminclude, for example, potassium carbonate, potassium hydrogen carbonate,etc. Such basic inorganic salts of magnesium include, for example, heavymagnesium carbonate, magnesium carbonate, magnesium oxide, magnesiumhydroxide, magnesium metasilicate aluminate, magnesium silicate,magnesium aluminate, synthetic hydrotalcite [Mg₆Al₂(OH)₁₆.CO₃.4H₂O],alumina hydroxide magnesium, and so forth. Among others, preferred isheavy magnesium carbonate, magnesium carbonate, magnesium oxide,magnesium hydroxide, etc. Such basic inorganic salts of calcium include,for example, precipitated calcium carbonate, calcium hydroxide, etc.

Such “solvents” include, for example, water for injection, alcohol,propylene glycol, macrogol, sesame oil, corn oil and olive oil.

Such “dissolution aids” include, for example, polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate andsodium citrate.

Such “suspending agents” include, for example, surfactants such asstearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, benzalkonium chloride, benzethonium chloride andmonostearic glycerol; and hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose andhydroxypropyl cellulose.

Such “isotonizing agents” include, for example, glucose, D-sorbitol,sodium chloride, glycerol and D-mannitol.

Such “buffers” include, for example, buffer solutions of phosphates,acetates, carbonates, citrates etc.

Such “soothing agents” include, for example, benzyl alcohol.

Such “preservatives” include, for example, p-oxybenzoic acid esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid andsorbic acid.

Such “antioxidants” include, for example, sulfites, ascorbic acid andα-tocopherol.

Such “coloring agents” include, for example, food colors such as FoodColor Yellow No. 5, Food Color Red No. 2 and Food Color Blue No. 2; andfood lake colors and red oxide.

Such “sweetening agents” include, for example, saccharin sodium,dipotassium glycyrrhetinate, aspartame, stevia and thaumatin.

Such “souring agents” include, for example, citric acid (citricanhydride), tartaric acid and malic acid.

Such “bubbling agents” include, for example, sodium bicarbonate.

Such “flavorings” may be synthetic substances or naturally occurringsubstances, and include, for example, lemon, lime, orange, menthol andstrawberry.

The crystal of the present invention may be prepared as a preparationfor oral administration in accordance with a commonly known method, by,for example, compression-shaping it in the presence of an excipient, adisintegrant, a binder, a lubricant, or the like, and subsequentlycoating it as necessary by a commonly known method for the purpose oftaste masking, enteric dissolution or sustained release. For an entericpreparation, an intermediate layer may be provided by a commonly knownmethod between the enteric layer and the drug-containing layer for thepurpose of separation of the two layers.

For preparing the crystal of the present invention as an orallydisintegrating tablet, acaliable methods include, for example, a methodin which a core containing crystalline cellulose and lactose is coatedwith the crystal of the present invention and a basic inorganic salt,and is further coated with a cating layer containing a water-solublepolymer, to give composition, which is coated with an enteric coatinglayer containing polyethylene glycol, further coated with an entriccoating layer containing triethyl citrate, still further coated with anentric coating layer containing polyethylene glycol, and still yetfurther coated with mannitol, to give fine granules, which are mixedwith additives and shaped. The above-mentioned “enteric coating layer”includes, for example, aqueous enteric polymer substrates such ascellulose acetate phthalate (CAP), hydroxypropylmethyl cellulosephthalate, hydroxymethyl cellulose acetate succinate, methacrylic acidcopolymers (e.g., Eudragit L30D-55 (trade name; produced by Rohm),Colicoat MAE30DP (trade name; produced by BASF), Polyquid PA30 (tradename; produced by San-yo Chemical)), carboxymethylethyl cellulose andshellac; sustained-release substrates such as methacrylic acid polymers(e.g., Eudragit NE30 D) trade name), Eudragit RL30D (trade name),Eudragit RS30 D (trade name), etc.); water-soluble polymers;Plasticizers such as methyl citrate, polyethylene glycol, acetylatedmonoglycerides, triacetin and caster oil; and mixtures thereof. Theabove-mentioned “additive” includes, for example, water-soluble sugaralcohols (e.g., sorbitol, mannitol, maltitol, reduced starchsaccharides, xylitol, reduced palatinose, erythritol, etc.), crystallinecellulose (e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH301, Avicel PH 302, Avicel RC-591 (crystalline Cellulose Carmellosesodium)), low-substituted hydroxypropyl cellulose (e.g., LH-22, LH-32,LH -23, LH-33 (Shin-Etsu Chemical) and mixtures thereof); binders,souring agents, bubbling agents, sweetening agents, flavorings,lubricants, coloring agents, stabilizers, excipients, disintegrants etc.are also used.

The crystal of the present invention may be used in combination with 1to 3 other active ingredients.

Such “other active ingredients” include, for example, anti-Helicobacterpylori activity substances, imidazole compounds, bismuth salts,quinolone compounds, and so forth. Of these substances, preferred areanti-Helicobacter pylori action substances, imidazole compounds etc.Such “anti-Helicobacter pylori action substances” include, for example,antibiotic penicillins (e.g., amoxicillin, benzylpenicillin,piperacillin, mecillinam, etc.), antibiotic cefems (e.g., cefixime,cefaclor, etc.), antibiotic macrolides (e.g., erythromycin,clarithromycin. etc.), antibiotic tetracyclines (e.g., tetracycline,minocycline, streptomycin, etc.), antibiotic aminoglycosides (e.g.,gentamicin, amikacin, etc.), imipenem. and so forth. Of thesesubstances, preferred are antibiotic penicillins, antibiotic macrolidesetc. Such “imidazole compounds” include, for example, metronidazole,miconazole, etc. Such “bismuth salts” include, for example, bismuthacetate, bismuth citrate, etc. Such “quinolone compounds” include, forexample, ofloxacin, ciploxacin, etc.

Such “other active ingredients” and the crystal of the present inventionmay also be used in combination as a mixture prepared as a singlepharmaceutical composition [e.g., tablets, powders, granules, capsules(including soft capsules), liquids, injectable preparations,suppositories, sustained-release preparations, etc.], in accordance witha commonly known method, and may also be prepared as separatepreparations and administered to the same subject simultaneously or at atime interval.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is hereinafter described in more detail by meansof, but is not limited to, the following reference examples, examplesand experimental examples.

In the following reference examples and examples, the term “roomtemperature” indicates about 15 to 30° C.

Melting points were measured using the Micro Melting Point Apparatus(produced by Yanagimoto Seisakusho), and uncorrected values are shown.

¹H-NMR spectra were determined with CDCl₃ as the solvent using VarianGemini-200; data are shown in chemical shift δ (ppm) from the internalstandard tetramethylsilane.

IR was determined using SHIMADZU FTIR-8200.

UV was determined using the HITACHI U-3200 spectrophotometer.

Optical rotation [α]_(D) was determined at 20° C. using the DIP-370digital polarimeter (produced by JASCO).

Optical purity was determined by HPLC (column: CHIRALCEL OD 4.6 mmdia.×250 mm, temperature: about 20° C., mobile phase:hexane/2-propanol=80/20 or hexane/2-propanol=85/15, flow rate: 1.0ml/min, detection wavelength: 285 nm) using achiral column.

Crystal X-ray diffraction data for determining the absolute structure ofsulfoxide were obtained by means of a 4-circle diffractometer (RIGAKUAFC5R) using the Cu-Kx_(α) ray. After the initial phase was determinedby the direct method, the fine structure was analyzed using SHELXL-93.X-ray powder diffraction was determined using the X-ray PowderDiffraction meter Rigaku RINT2500 (ultraX18) No. PX-3.

The other symbols used herein have the following definitions:

s: singlet

d: doublet

t: triplet

q: quartet

m: multiplet

bs: broad singlet

J: binding constant

EXAMPLES Reference Example 1 Isolation of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(R(+)-lansoprazole)

2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(lansoprazole) (racemate) (3.98 g) was dissolved in the following mobilephase (330 ml) and acetonitrile (37 ml) and fractionated by HPLC(column: CHIRALCEL OD 20 mm dia.×250 mm, temperature: 30° C., mobilephase: hexane/2-propanol/ethanol=255/35/10, flow rate: 16 ml/min,detection wavelength: 285 nm, 1 shot: 20-25 mg). Fractions of opticalisomers of shorter retention time were combined and concentrated; theindividual lots were combined and dissolved in ethanol and filteredthrough a 0.45 μm filter; after hexane was added, the filtrate was againevaporated to dryness to yield R(+)-lansoprazole (1.6 g, opticalpurity >97.6% ee) as an amorphous substance.

The amorphous substance obtained was subjected to fractionation andisolation in the same manner as above to yield R(+)-lansoprazole (1.37g, optical purity >99.9% ee) as an amorphous substance.

[α]_(D)=+174.3° (c=0.994%, CHCl₃)

Reference Example 2 Isolation of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(R(+)-lansoprazole)

Lansoprazole (racemate) (34.2 g) was dissolved in 2-propanol (1,710 ml)and hexane (1,140 ml) containing triethylamine(0.2%) and fractioned byHPLC (column: CHIRALCEL OD 50 mm dia.×500 mm, temperature: roomtemperature, mobile phase: hexane/2-propanol=85/15, flow rate: 60ml/min, detection wavelength: 285 nm, single injection: about 300 mg) toisolate the individual optical isomers. Fractions of an optical isomerof shorter retention time were combined and concentrated; the individuallots were combined and dissolved in ethanol (250 ml); aftertriethylamine (3 ml) was added, the solution was filtered through a 0.45μm filter. After the filtrate was concentrated, hexane was added, andthe filtrate was again evaporated to dryness to yield R(+)-lansoprazole(9.31 g. optical purity 98.3% ee) as an amorphous substance.

Reference Example 3 Production of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(R(+)-lansoprazole)

In a nitrogen atmosphere.2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole(20.0 g, 0.057 mol), toluene (100 ml), water (55 mg, 0.0031 mol as basedon total water content) and diethyl(+)-tartrate (2.12 ml, 0.012 mol)were mixed and stirred at 50 to 55° C. for 30 minutes. After titanium(IV) isopropoxide (1.66 ml, 0.0057 mol) was added to the mixture in anitrogen atmosphere, the mixture was stirred at 50 to 55° C. for 1 hour.After diisopropylethylamine (3.25 ml, 0.019 mol) was added to theresulting mixed liquor under cooling in a nitrogen atmosphere, cumenehydroperoxide (30.6 ml, content 82%, 0.17 mol) was added at 0 to 5° C.,followed by 3.5 hours of stirring at 0 to 5° C., to cause the reaction.

Analysis of the reaction liquor by HPLC (column: CHIRALCEL OD (DaicelChemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flowrate: 1.0 ml/min, detection wavelength: 285 nm) detected a sulfide at1.32% and a sulfone at 1.81% as related substances in the reactionliquor, with no other related substances detected. The enantiomer excessrate of the title compound in said reaction liquor was 96.4% ee.

Reference Example 4 Crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(R(+)-lansoprazole)

(1) In a nitrogen stream,2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole(4.5 kg, 12.7 mol, containing 1.89 g of water), toluene (22 l), water(25 g, 1.39 mol, or 1.49 mol if based on total water content) anddiethyl (+)-tartrate (0.958 l, 5.60 mol) were mixed. In a nitrogenstream, titanium (IV) isopropoxide (0.747 l, 2.53 mol) was added to thismixture at 50 to 60° C., and the mixture was stirred at the abovetemperature for 30 minutes. After diisopropylethylamine (0.733 l, 4.44mol) was added to the resulting mixed liquor at room temperature in anitrogen stream, cumene hydroperoxide (6.88 l, content 82%, 37.5 mol)was added at −5 to 5° C., followed by 1.5 hours of stirring at −5 to 5°C., to yield a reaction liquor.

Analysis of the reaction liquor by HPLC (column: Capcell Pak (Shiseido,Co. Ltd.), mobile phase: solvent mixture(acetonitrile/water/triethylamine=50/50/1); adjusted to pH 7.0 withphosphoric acid, flow rate: 1.0 ml/min, detection wavelength: 285 nm)detected a sulfide at 1.87% and a sulfone at 1.59% as related substancesin the reaction liquor, with no other related substances detected.

(2) To the reaction liquor obtained in (1) above, a 30% aqueous solutionof sodium thiosulfate (17 l) was added, in a nitrogen stream, todecompose the residual cumene hydroperoxide. To the organic layerobtained by liquid separation, water (4.5 l), heptane (13.5 l), t-butylmethyl ether (18 l) and heptane (27 l) were added sequentially in thisorder, and this mixture was stirred to cause crystallization. Theresulting crystal was separated and washed with t-butyl methylether-toluene (t-butyl methyl ether:toluene=4:1) (4 l) to yield a wetcrystal of (R)-lansoprazole having the following powder X-raydiffraction interplanar spacings (d).

The results of powder X-ray diffraction analysis of this wet crystal areshown below.

The wet crystal yielded a powder X-ray diffraction pattern withcharacteristic peaks appearing at powder X-ray diffraction interplanarspacings (d) of 5.85, 4.70, 4.35, 3.66 and 3.48 Angstrom.

Analysis of this crystal by HPLC (column: CHIRALCEL OD (Daicel ChemicalIndustries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 1.0ml/min, detection wavelength: 285 nm) detected a sulfone at 0.90% as arelated substance in the crystal, with no sulfide or any other relatedsubstance detected. The (R)-lansoprazole enantiomer excess rate in thiscrystal was 100% ee.

(3) With stirring, a suspension in acetone (20 l) of the wet crystalobtained in (2) above was added drop by drop into a mixed liquor ofacetone (7 l) and water (34 l), then water (47 l) was added. Theprecipitated crystal was separated and washed with acetone-water(acetone:water=1:3) (4 l) and water (12 l) to yield a wet crystal of(R)-lansoprazole having the following powder X-ray diffractioninterplanar spacings (d).

The results of powder X-ray diffraction analysis of this wet crystal areshown below.

The wet crystal yielded a powder X-ray diffraction pattern withcharacteristic peaks appearing at powder X-ray diffraction interplanarspacings (d) of 8.33, 6.63, 5.86 and 4.82 Angstrom.

Analysis of this crystal by HPLC (column: CHIRALCEL OD (Daicel ChemicalIndustries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 1.0ml/min, detection wavelength: 285 nm) detected no sulfone, sulfide orany other related substance in the crystal. The (R)-lansoprazoleenantiomer excess rate in this crystal was 100% ee.

(4) After the wet crystal obtained in (3) above was dissolved in ethylacetate (45 l) and water (3 l), this solution was divided into liquidlayers. The trace amount of insoluble matter in the organic layer wasfiltered off, then triethylamine (0.2 l) was added, after which thefiltrate was concentrated under reduced pressure to a liquid volume ofabout 7 l. To this concentrate, methanol (2.3 l), about 12.5% aqueousammonia at about 50° C. (23 l) and t-butyl methyl ether at about 50° C.(22 l) were added, and this liquid was divided into layers. To theorganic layer, about 12.5% aqueous ammonia (11 l) was added, and thisliquid was divided into layers (this operation was repeated once again).The water layers were combined, and ethyl acetate (22 l) was added, andthen acetic acid was added drop by drop to reach a pH of about 8 undercooling. The liquid was divided into layers, and the water layer wasextracted with ethyl acetate (11 l). The organic layers were combinedand washed with about 20% saline (11 l). After triethylamine (0.2 l) wasadded, the organic layer was concentrated under reduced pressure.Acetone (5 l) was added to the concentrate, and this mixture wasconcentrated under reduced pressure. The concentrate was dissolved inacetone (9 l), and this solution was added drop by drop into a mixedliquor of acetone (4.5 l) and water (22.5 l), and then water (18 l) wasadded drop by drop to the mixed liquor obtained. The precipitatedcrystal was separated and washed sequentially with cold acetone-water(acetone:water=1:3) (3 l) and water (12 l) to yield a wet crystal of(R)-lansoprazole having the following powder X-ray diffractioninterplanar spacings (d).

The results of powder X-ray diffraction analysis of this wet crystal areshown below.

The wet crystal yielded a powder X-ray diffraction pattern withcharacteristic peaks appearing at powder X-ray diffraction interplanarspacings (d) of 8.33, 6.63, 5.86 and 4.82 Angstrom.

Analysis of this crystal by HPLC (column: CHIRALCEL OD (Daicel ChemicalIndustries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 1.0ml/min, detection wavelength: 285 nm) detected no sulfone, sulfide orany other related substance in the crystal. The (R)-lansoprazoleenantiomer excess rate in this crystal was 100% ee.

(5) The wet crystal obtained in (4) above was dissolved in ethyl acetate(32 l). The water layer was separated by a liquid separation procedure,and the organic layer obtained was concentrated under reduced pressureto a liquid volume of about 14 l. To the residual liquid, ethyl acetate(36 l) and activated charcoal (270 g) were added, after stirring, theactivated charcoal was removed by filtration. The filtrate wasconcentrated under reduced pressure to a liquid volume of about 14 l. Atabout 40° C., heptane (90 l) was added drop by drop to the residualliquid. After stirring at the above temperature for about 30 minutes,the resulting crystal was separated, washed with about 40° C. ethylacetate-heptane (ethyl acetate:heptane=1:8) (6 l), and dried to yield3.4 kg of the title compound.

The results of powder X-ray diffraction analysis of this crystal areshown below.

The crystal yielded a powder X-ray diffraction pattern withcharacteristic peaks appearing at powder X-ray diffraction interplanarspacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69,3.41 and 3.11 Angstrom.

Analysis of this crystal by HPLC (column: CHIRALCEL OD (Daicel ChemicalIndustries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 1.0ml/min, detection wavelength: 285 nm) detected no sulfone, sulfide orany other related substance in the crystal. The (R)-lansoprazoleenantiomer excess rate in this crystal was 100% ee.

Example 1 Crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(R(+)-lansoprazole)

Amorphous R(+)-lansoprazole as obtained in Reference Example 1 (100 mg)was dissolved in acetonitrile (1 ml), which was gradually evaporated atroom temperature in a nitrogen stream. After a crystal began to form,diethyl ether (1.5 ml) was added and the container was stoppered andkept standing at room temperature.

The crystal thus formed was subjected to X-ray structural analysis, andthe absolute configuration of sulfoxide was found to be theR-configuration by a method using a Flack parameter. The remainingportion of the crystal was collected by filtration, twice washed withdiethyl ether (1 ml), and dried under reduced pressure, to yieldcrystals of R(+)-lansoprazole (38 mg).

m.p.: 144.0-144.5 DC-(dec.)

Elemental Analysis

Calculated: C, 52.03; H, 3.82; N, 11.38; S, 8.68; F, 15.43; O, 8.66

Found: C, 52.08; H, 3.76; N, 11.58; S, 8.75; F, 15.42.

¹H-NMR: 2.25 (3H: s), 4.40 (2H, q, J=7.8 Hz), 4.68 (1H, d, J=13.8 Hz),4.85 (1H, d, J=13.8 Hz), 6.69 (1H, d, J=6.0 Hz), 7.29-7.39 (2H, m), 7.52(1H, m), 7.81 (1H, m), 8.37 (1H, d, J=6.0 Hz), 11.00 (1H, bs).

IR(ν cm⁻¹l): 3081, 3042, 2984, 1586, 1478, 1441, 1306, 1267, 1163.

UVmax(CHCl₃): 283.7 nm

[α]_(D)=+199.2°(c 0.202%, CHCl₃)

TABLE 1 Crystal Data and Structure Refinement Parameters Molecularformula C₁₆H₁₄N₃O₂F₃S Molecular weight   369.36 Crystal color, habitColorless, tabular Crystal Dimension    0.40 × 0.30 × 0.04 (mm) Crystalsystem Monoclinic Lattice constants a = 8.549(1) (Å) b = 23.350(1) (Å) c= 8.720(2) (Å) β = 103.90(1) (°) V = 1,689.8(4) (Å) Space group P2₁ Z   4 Density (calculated)    1.452 (g/cm³) Effective reflectionnumber/parameter number    9.12 R (I ≧ 2σ(I))    0.036 Flack parameter −0.02(2)

Example 2 Crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(R(+)-lansoprazole)

Amorphous(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleas obtained in Reference Example 2 (9.17 g) was dissolved in acetone (20ml), and water (15 ml) was added with gentle heating. After the solutionwas kept standing at room temperature overnight, water (20 ml) wasadded, followed by ultrasonication. After being collected by filtration,the solid was washed with water (30 ml, 20 ml), then washed withdiisopropyl ether (20 ml), and dried under reduced pressure, to yield asolid (9.10 g). The solid obtained (9.00 g) was dissolved in acetone (30ml), and after the solution was filtered, diisopropyl ether (50 ml) wasadded to the filtrate. A crystal seed was placed, and the mixture waskept standing at room temperature overnight. Precipitated crystals werecollected by filtration, washed 3 times with diisopropyl ether (10 ml),and dried under reduced pressure, to yield crystals (7.85 g). Thecrystals obtained (7.80 g) were dissolved under heating in acetone (22.5ml) and water (30 ml), and this solution was kept standing at roomtemperature for 1 hour. A precipitated solid was collected byfiltration, washed with acetone-water (1:4) (15 ml), and dried underreduced pressure, to yield a solid (3.88 g). The solid obtained (3.88 g)was dissolved under heating in acetone (4 ml) and diisopropyl ether (14ml) was added. This solution was kept standing at room temperature for30 minutes. Precipitated crystals were collected by filtration, twicewashed with diisopropyl ether (6 ml), and dried under reduced pressure,to yield crystals of R(+)-lansoprazole (3.40 g, optical purity 99.8%ee).

m.p.: 147.0-148.0° C. (dec.)

Elemental Analysis

Calculated: C, 52.03; H, 3.82; N, 11.38; S, 8.68; F, 15.43; O, 8.66.

Found: C, 51.85; H, 3.92; N, 11.26; S, 8.82; F, 15.22.

¹H-NMR: 2.24 (3H, s), 4.38 (2H, q, J=7.8 Hz), 4.74 (1H, d, J=13.6 Hz),4.87 (1H, d, J=13.6 Hz), 6.68 (1H, d, J=5.8 Hz), 7.26-7.36 (2H, m), 7.45(1H, m), 7.78 (1H, m), 8.35 (1H, d, J=5.8 Hz). IR(ν cm⁻¹l): 3083, 3034,2975, 1586, 1478, 1441, 1306, 1267, 0.1163

UVmax(CHCl₃): 283.6 nm

[α]_(D)=+180.30 (c=1.004%, CHCl₃)

TABLE 2 X-ray Powder Diffraction Data Half-value Relative 2θ (°) widthd-value (Å) intensity (%) 7.560 0.141 11.6841 100 13.060 0.165 6.7733 4415.160 0.141 5.8394 55 15.440 0.141 5.7342 84 20.040 0.165 4.4271 2321.720 0.165 4.0883 89 22.560 0.141 3.9380 24 22.820 0.141 3.8937 2424.080 0.165 3.6927 37 26.120 0.118 3.4088 32 28.680 0.165 3.1100 20

Example 3

Crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(R(+)-lansoprazole) 1.5 hydrate

Amorphous(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleas obtained in Reference Example 1 (100 mg) was dissolved in ethanol(0.15 ml), and water. (0.15 ml) was added. After a seed was placed, thesolution was kept standing at room temperature for 1 hour. Precipitatedcrystals were collected by filtration, twice washed with water (2 ml),and dried under reduced pressure, to yield crystals of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(R(+)-lansoprazole) 1.5 hydrate (96 mg).

m.p.: 76.0-80.0° C.

Elemental Analysis

Calculated: C, 48.48; H, 4.32; N, 10.60; S, 8.09; F, 14.38; O, 14.13.

Found: C, 48.52; H, 4.44; N, 10.49.

TABLE 3 X-ray Powder Diffraction Data Half-value Relative 2θ (°) widthd-value (Å) intensity (%) 6.680 0.165 13.2212 9 9.200 0.165 9.6046 219.960 0.141 8.8734 25 10.980 0.165 8.0513 42 13.380 0.141 6.6120 2214.960 0.141 5.9170 63 15.680 0.165 5.6469 100 17.640 0.212 5.0237 3419.760 0.212 4.4892 33 25.420 0.188 3.5010 23 29.800 0.188 2.9957 20

Experimental Example 1

Suppressive Action on Gastric Mucosal Injury Due to Stress of WaterImmersion Restraint in Rat

Male SD rats (7 weeks of age, weighing 230 to 250 g) were fasted for 24hours, after which they were stressed by being housed in restraint cagesand immersed to below the xiphoid process in a standing position in a23° C. constant-temperature water chamber. After 5 hours, the rats wereremoved from the cages and sacrificed using gaseous carbon dioxide, andtheir stomachs excised. After the lower portion of the esophagus wasclipped, a 1% formalin solution (10 ml) was injected into the stomachvia the duodenum, which was then occluded, and the stomach was immersedin the same solution. After 10 minutes, an incision was made along thegreater curvature, and the length (mm) of each mucosal injury wasmeasured under a stereomicroscope. The overall sum of the injury lengthsin each stomach was taken as the gastric mucosal injury index.

The crystals of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(R(+)-lansoprazole) as obtained in Example 2 were suspended in 0.5%methyl cellulose (pH 9.5) containing 0.05 M NaHCO₃ and orallyadministered at 30 minutes before stressing (dosing volume 2 ml/kg).Each treatment group comprised 9 animals. The control group (solventadministration group) and the drug administration group were compared bySteel's test.

The results are shown in Table 4.

TABLE 4 Dose Gastric mucosal Suppression Sample (mg/kg) injury index(mm) rate (%) Control — 10.9 ± 1.9 — (R)-lansoprazole 3  0.2 ± 0.2* 98.0crystal Each figure of gastric mucosal injury index is the mean ±standard error for the 9 animals in each group. *p < 0.01 (versuscontrol group, Steel's test)

Experimental Example 2

The crystals of R(+)-lansoprazole as obtained in Example 2 (about 5 mg)and amorphous R(+)-lansoprazole as obtained in Reference Example 1(about 5 mg) were each taken in a colorless glass bottle, and theirstability during storage at 60° C. (stopper removed) was examined. A 25ml solution (concentration: about 0.2 mg/ml) of the sample aftercompletion of storage in the mobile phase, along with a standardsolution prepared using the initial lot, was analyzed under the HPLCconditions shown below, and the R(+)-lansoprazole content (residualpercentage) was calculated from the peak area obtained. The results areshown in Table 5.

HPLC analytical conditions Detection wavelength UV 275 nm Column YMC ProC18, 4.6 × 150 mm Mobile phase Fluid prepared by adding phosphoric acidto water/acetonitrile/triethyl amine (63:37:1) to reach pH 7. Flow rate 1.0 ml/min Column temperature 40° C. Sample injection volume 10 μl

TABLE 5 Stability of R(+)-Lansoprazole Crystal and Amorphous Duration ofContent (Residual Sample storage Description percentage) Crystal 1 weekLight-brown 97.0 2 weeks Brown 93.8 4 weeks Brown 91.7 Amorphous 1 weekBrown 70.8 2 weeks Blackish brown 57.5

When the sample was stored at 60° C. (exposed), the crystal of Example 2retained a content exceeding 90% for up to 4 weeks, whereas theamorphous form of Reference Example 1 showed reduction in content to70.8% after 1 week and 57.5% after 2 weeks. This finding demonstratesthat the crystal of R(+)-lansoprazole is more stable and more preferablefor use as a pharmaceutical etc. than the amorphous form.

INDUSTRIAL APPLICABILITY

The crystal of the present invention is useful as a pharmaceuticalbecause it shows excellent antiulcer action, gastric acidsecretion-inhibiting action, mucosa-protecting action, anti-Helicobacterpylori action etc., and because it is of low toxicity. Furthermore, bycrystallizing the (R)-isomer, not only its stability is improved butalso its handling is facilitated so that it can be prepared as a solidpharmaceutical composition with good reproducibility. In addition, whenorally administered, the crystal of the present invention is moreabsorbable and more rapidly shows its action than the racemate. Inaddition, when administered, the crystal of the present invention showsa higher Cmax and a greater AUC than the racemate, and becomes lesslikely to be metabolized partly because of the increased protein-bindingrate, thus showing an extended duration of action. The crystal of thepresent invention is therefore useful as a pharmaceutical of low dosageand with a low prevalence of adverse reactions.

1. A method for manufacturing a preparation for oral administration,which comprises: formulating a crystal of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof and a pharmaceutically acceptable carrier into a firstcomposition; and subsequently forming the preparation for oraladministration.
 2. The method according to claim 1 wherein the X-raypowder diffraction analysis pattern of the crystal has characteristicpeaks at the interplanar spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43,4.09, 3.94, 3.89, 3.69, 3.41, and 3.11 Angstrom.